Pre-exposure prophylaxis (PrEP) refers to daily or intermittent oral administration of antiretroviral drugs designed to protect high-risk HIV-negative individuals from infection. As PrEP is, at present, the most promising biomedical prevention tool, the Centers for Disease Control and Prevention (CDC) is currently reviewing PrEP data and developing detailed public health guidelines for its safe and effective use. Any roll-out of PrEP to MSM in the U.S. will require the development of messages that facilitate understanding of partial efficacy, proper administration, and sustained risk reduction practice. Although the swift development of PrEP-specific interventions is critical, we currently lack basic knowledge about unique cognitive, affective, and behavioral dynamics that may make a significant difference in both efficacy and effectiveness of PrEP as a biomedical prevention strategy. This project applies empirical findings and theoretical models from behavioral economics, social psychology, decision-sciences, health communication, and neuroeconomics to the development of PrEP messaging and communication strategies, in order to: (1) Examine the independent and cumulative impact of four elements of PrEP messaging - modality, frame, specificity, and messenger - on comprehension and acceptability of PrEP as a biomedical prevention strategy;(2) Estimate the impact of each of these factors on individual risk-perception and predicted sexual behavior in the context of PrEP use;(3) Identify individual-level factors, (i.e. demographics, risk tolerance, health numeracy), that might moderate the impact of message factors on comprehension, acceptability, risk perception, or risk compensation;and (4) Provide specific recommendations regarding the optimal message elements and communication strategies for PrEP in order to maximize comprehension and acceptability, while positively impacting risk perception and reducing the likelihood of risk compensation. To accomplish these aims, we will enroll 800 MSM living in the New York City area and randomly assign them to experimental conditions in a 2x2x2x2 factorial design. Data collection will include ACASI measures of outcomes (comprehension, acceptability, risk perception, and risk compensation) as well as potential moderators in four areas: (a) dispositional;(b) cognitive;(c) affective/motivational;and (d) behavioral (sexual risk and substance use). In addition, we will conduct 2 focus groups with each of 5 "special interest groups" (e.g. transgender women, serodiscordant couples) in order to gather detailed data regarding the specific needs, concerns, and issues among populations most likely to be offered PrEP. The proposed project has the potential to exert a sustained and powerful influence not only on the development of PrEP-specific messaging, but also on our understanding of the cognitive and affective processes underlying comprehension of risk-reduction messages, risk perception, and risk compensation. PUBLIC HEALTH RELEVANCE: Pre-exposure prophylaxis (PrEP) is a new biomedical approach to HIV prevention with the potential to become a powerful tool. This study examines specific elements of PrEP messaging and communication hypothesized to have a significant impact on comprehension, acceptability, risk perception, and risk compensation. Study findings have the potential to move the field toward a more interdisciplinary approach to understanding the behavioral mechanisms that underlie acceptability and adherence to biomedical prevention strategies.